Just recently our ICU team was called to the wards to look at a 74 year old gentlemen with sudden shortness of breath and low peripheral saturations. He was known to suffer of hypertensive heart disease and now presented with acute pulmonary oedema. After giving oxygen over a non-rebreathing mask he was administered furosemide (Lasix) intravenously and brought to the unit for non-invasive ventilation.

​Interestingly a discussion started on whether giving Lasix as a first line agent in the acute setting of pulmonary oedema is beneficial or not. A quick look into to current literature gave no clear answer and reading further into the topic revealed amazing properties of Lasix we hadn't been really aware of so far. We all use and love Lasix, but do we really know the drug?​

The Beginning of Lasix

Furosemide (sometimes also called frusemide) was first developed by 'Farbwerke Hoechst AG' in Frankfurt am Main, Germany, a company that was founded back in the year 1863. Karl Stürm, Walter Siedel and Rüdi Weyer set the basis with the invention of N-substituted-3-Carboxy-6-Halo-Sulfanilamide and it's derivates, one of them being furosemide. The researchers soon noticed its saluretic (sodium Na, potassium K and chloride Cl) and diuretic effect in almost equivalent proportions. As these substances did not cause any acidosis nor alkalosis they suggested their future usage for the treatment of oedema and hypertension.

The Naming of Furosemide

Researchers soon noticed that the diuretic effect of furosemide lasted for about 6 hours... 'LAsts for SIX hours'... and therefore gave it the name: LASIX!​

Furosemide can be applied by oral intake as a tablet or as an intravenous injection. Once in the blood stream it is predominantly bound to proteins (>90%).

Loop diuretics do not undergo glomerular filtration. In fact they pass the glomerulus and are actively secreted across proximal tubular cells by organic anion transporters and the multidrug resistance associated protein 4 (area A). It is important to know that non-steroidal anti-inflammatory drugs (NSAID) and endogenous uremic anions compete with this loop diuretic secretion and can cause 'diuretic resistance'.

Once loop diuretics have reached the tubular system they bind to to sodium-potassium-chloride co-transporters (NKCC2) in the ascending limb of the loop of Henle and block the reabsorption of these ions directly (area B). Further down at the macula densa they inhibit the same co-transporter (area B) thereby stimulating renin secretion and inhibiting tubuloglomerular feedback. This results in preserved glomerular filtration despite increased salt delivery to the macula densa. All this finally results in the loss of sodium, chloride and potassium and therefor loss of water.

Other Effects

Furosemide also interacts with other sodium-potassium-chloride co-transporters (NKCC1) elsewhere in the body:- Blocking NKCC1 in the ear probably explains the ototoxicity of loop diuretics- Blocking NKCC1 in smooth muscle cells causes vasodilation​- Blocking NKCC1 in the afferent arteriole and near the macula densa elevates renin secretion and the generation of angiotensin II

These complex interactions on haemodynamics explain that the net response in each patient might be different. On the one hand loop diuretics dilate blood vessels directly and increase the level of vasodilatory prostaglandins. On the other hand some of these effects counteract each other making it difficult to predict which effect will finally predominate.

Many studies have looked closer into the vasoactive properties of furosemide. Current evidence indicates that it has systemic venodilator effect which actually reduced preload acutely. The same investigators found a reduction in the right atrial pressure and the pulmonary capillary wedge pressure, presumably reflecting the systemic venodilator effect of furosemide.

While the acute venodilator effect may be beneficial to the failing heart its action on arteries might be detrimental. Several studies have shown that in patients with chronic heart failure furosemide causes arterial vasoconstriction. Also there is one study showing that pulmonary vascular resistance in healthy volunteers rose significantly.

Administered orally furosemide has a limited and highly variable bioavailability. The diuretic effect starts within the first hour and the duration of action is around 6 hours (4-8 hours). Injected intravenously furosemide is approximately twice as potent on per-miligramm basis as oral doses.

In acute decompensated heart failure sodium retention becomes more avid and higher peak levels might be required to become more effective. This can be achieved by giving furosemide intravenously.

Once a loop diuretic is administered, the excretion of sodium chloride is increased for several hours. This is then followed by a period of very low sodium excretion resulting in a so called 'post-diuretic retention'.

How to use Furosemide for Acute Decompensated Heart Failure (ADHF)

So far for the basics of furosemide, but what about it's usage for acutely decompensated heart failure? Should furosemide be given as soon as possible or not?

The 2013 ACCF/AHA guidelines for the management of patients with heart failure give diuretics a class I recommendation. The evidence behind these recommendations though is level B or level C only! So these recommendations are not really helpful to answer this question.

The authors in UpToDate® mention diuretics directly after the use of oxygen. For patients with evidence of volume overload their recommendation is to give loop diuretics immediately (Grad 1B) as there is evidence that in this setting this may improve outcomes. They also suggest that patients with ADHF usually are volume overloaded, therefor suggesting that most patients should receive diuretics ASAP. The only exception they mention where some delay in inducing diuresis might be required is in patients with severe hypotension or cardiogenic shock.

There is reasonable doubt that patients with ADHF are usually volume overloaded, as suggested by UpToDate®. Zile MR et al. demonstrated that while most patients with acute pulmonary oedema have increased filling pressures, most did not have significant increases from their dry weight on presentation! Fallick et al. actually argue that it isn't fluid gain but rather shift in fluids from other compartments, particularly shift from the splanchnic circulation, which is normally very compliant.

In conclsion there is no straight forward answer to this question but I would put it down as follows:​​

​​- Furosemide should not be routinely used for the immediate treatment of acute decompensated heart failure (ADHF)/ acute pulmonary oedema

- However, in patients with evidence of volume overload the administration of early furosemide (preferentially given as an intravenous bolus) seems beneficial and improves outcome. But beware, most patients are not volume overloaded!

- In urgent situations the focus should be on early non-invasive ventilation and the administration of nitroglycerin!

Postoperative pain and delirium is a common concern and currently approached by different interventions. There is some evidence suggesting that ketamine given intra-operatively might have an influence on postoperative pain and delirium. Some anaesthetists commonly give a single dose of ketamine intra-operatively for exactly this reason.

Thumbs up for Ket

Ketamine has kept its fascination in various settings, from retrieval medicine onto the the care of critically ill patients in the ICU. Ketamine reduces postoperative markers of inflammation, is a rapid-acting antidepressant drug with an effect lasting for several days and might have neuroprotective properties.

Ketamine also has become increasingly popular as an adjunct to other sedatives in the ICU. There is evidence showing that ketamine used in the ICU has the potential to reduce cumulative opioid consumption after surgery (Asad E. et al. J Intensive Care Med December 8 2015 ).

Even better: It does not cause any kidney injuries, preserves laryngeal protective reflexes, lower airway resistance and much more...

And: Ketamine is cheap and has been used safely for over 50 years by anaesthetists!

The Dark Side of Ket

But there's the other side of ketamine making all of this a little more complicated. After all, Ketamine is a psychoactive drug and has well known hallucinogenic properties. Developed in the 1960s as a dissociative anaesthetic agent it started to appear on the street in the early 1970s and made its way to the 1980s as Special K, Acid and Super C (Dotson JW et al. J of Drug Abuse, Vol 25, Issue 4, 1995).

Participants, clinicians, and investigators were blinded to group assignment. They found

NO difference in in the incidence of postoperative delirium among these groups

but

significantly more postoperative hallucinations and nightmares with increasing ketamine doses compared to placebo

This trial seems well performed with an acceptable sample size. The application of a single dose of ketamine before surgery neither prevented delirium nor induced it. With this sample size it seems safe to say that even if ketamine does prevent delirium, its effect would be rather small.

Furthermore, postoperative pain was not influenced by giving a single dose of ketamine and this is in contrast to previous findings and current guidelines. Importantly, most of the previous studies are smaller than this trial, making these findings remarkable.

But what really drew my attention was the fact that the appearance of hallucinations and night-mares was increased for at least 3 days after surgery.

So if ketamine has no influence on postoperative delirium or pain but does induce hallucinations and nightmares, even 3 days after surgery, current guidelines might have to be revised.

The Bottom Line

- The application of a subanaesthetic dose of ketamine during surgery to tackle postoperative pain and delirium does not seem to be as effective as previously assumed

- The usage of ketamine in this setting even seems to have undesirable side-effects like hallucinations and nightmare - and this effect might even last for up to 3 days!

- This trial provides good reasons to look for other options to prevent postoperative delirium!

(Like dexmedetomidine? The answer to this question has just been answered: READ HERE!)

Sometimes there's this moment you read about medical research in the news... sometimes you read lots of rubbish on medical issues in the news... but sometimes you stop and read, and you don't know what to think. This happened to quite some of us a couple of days ago when reading the headlines in the British Independent:

Well, it's not very often you read the term sepsis in the news but the word 'cure' causes estonishment or rather misbelief. Further reading certainly catches your attention: 'A doctor in the US state of Virginia claims to have found his own cure for sepsis' and 'Since then, he has used it to treat 150 sepsis patients. Just one has died of the condition, claims Dr Marik'. And it's not an article from some remote pseude magazine... no, it has been published in 'Chest'! And all this is not due to some novel molecule... it's all about Vitamin C!

Thanks to #FOAMed quite some smart brains have looked into this topic already...

47 septic patients treated in their unit during the preceding 7 months

They performed

Propensity score matching

and found

An overall hospital mortality of 40.4% in the control group compared to 8.5% in the intervention group

This means

An absolute risk reduction of 31.9% and also according to the authors none of the patients in the intervention arm died of sepsis!

What Does This Mean?

These results are quite amazing on the first look, but there's more behind these numbers. Paul Marik has first of all published an observational study: unblinded, uncontrolled, retrospective and low in patient numbers.

There are several limitations that go hand in hand with studies as such and unblinded before-and-after studies have a lot. A major challenge in conducting observational studies is to draw inferences that are acceptably free from influences by overt biases, as well as to assess the influence of potential hidden biases. One of the biggest drawbacks in this current study is the timely/ seasonal difference when patients have been selected.If you are interested to have a closer look on this you should read Dan's blog entry on stemlynsblog.org HERE.

Studies like this one are an important part of science, but observational studies are observational... not proof!​

Why Vitamin C in Sepsis?

There is a scientific rationale behind all of this. As mentioned by Paul in his paper vitamin C levels do fall low in sepsis and the most efficient way to administer it is intravenously. The same is true for thiamin which also goes low in up to one third of all septic patients.

There are two rather small randomised control trials suggesting that vitamin C is safe in septic patients and might actually be of some degree of benefit for the patient.

- Is an important conenzyme for the procollagen-proline dioxygenase, which itself is necessary for the biosynthesis of stable collagen in our body. Vitamin C deficiency leeds to unstable collagen and therefore scurvy

- Is an important cofactor in the synthesis of steroids like cortisol and catecholamines like dopamine and noradrenalinas well

- and it has many more functions that go beyond the scope of this blog entry!

However, the importance of vitamin C in the treatment and prevention of diseases like e.g. the common cold or influenza remains highly contrversial. The observation of some moderate positive influence on the course of disease in some studies could not be reproduced in other trials.

Under normal circumstances vitamin C deficiency is practically non-existent in Europe, but becomes a fact during sepsis. If this is clinically relevant in septic patients seems plausible but remains to be elucidated.

More Ifs and Buts

Sepsis is not a disease, its a clinical syndrome that has physiologic, biologic and biochemical abnormalities caused by a dysregulated inflammatory response to infection. The fact that different definitions have evolved since the early 1990s shows that we still struggle to definde sepsis as a single entity. This is one reason why a single therapy might not always be the best for each diesease causing sepsis.

Paul Marik’s publication is interesting and deserves respect. It’s an observational study but provides no evidence by far. Vitamin C might be an interesting novel approach to sepsis but the term ‘cure’ used in the media is inappropriate and misleading.

The term ‘cure for sepsis’ also implicates that vitamin C is a cure for all infections causing sepsis and is therefore problematic.​

The Current Bottom Line

​- The study published by Marik et al. is purely observational and provides no proof at all.

- Just because vitamine C might be safe in Sepsis does not mean this has to be given. At this stage no recommendation can be made for the use of vitamin C in sepsis.

- Studies like these are an part of research itself - However, the use of the term 'cure' seem problematic and inappropriate in this context.

When filling out the form for a CT scan in you hospital you will not only have to provide clinical information about the patient but almost certainly also the latest creatinine levels. This information is required as many clinicians are worried that IV contrast media might cause iatrogenic acute kidney injury and therefore increased rates of dialysis, renal failure, and death. Despite several reports of contrast-induced nephropathies in the past, the causal relationship between IV contrast media and the development of acute kidney injury has been challenged recently (Read our previous summary​HERE).

​The major problem is that performing a randomized controlled trial to elucidate the true incidence of contrast-induced nephropathy is considered unethical because of the presumption that contrast media administration is a direct cause of acute kidney injury.

While the discussion goes on Hinson et al. have come up with another nice piece of evidence that in emergency situations there is no reason to withhold the application of IV contrast for CT scans when required.

​In this single-center retrospective cohort study researchers have included a total of 17'934 patient visits to their emergency department over a period of 5 years. They analysed three patient groups that where demographically similar: contrast-enhanced CT, unenhanced CT and no CT scan performed. Patients were included when their initial serum creatinine level was between 35 umol/L and 352 umol/L. Of all CT scans, 57.2 percent were contrast-enhanced. The probability of developing acute kidney injury was 6.8 percent for patients undergoing contrast-enhanced CT, 8.9 percent for patients receiving unenhanced CT and 8.1 percent for patients not receiving CT at all. This proofs to be the largest controlled study of its kind in the emergency department and shows that:

In current clinical context, contrast media administration for CT scans is NOT associated with an increased incidence of acute kidney injury. And even though a large randomised controlled trial is still missing it seems safe...

​To Conclude:​There is no reason to withhold the use of IV contrast media in cases where contrast-enhanced CT is indicated to avoid delayed or missed diagnosis of critical disease.

For the resuscitation out-of-hospital one of the mainstays besides compression and defibrillation ist the application of adrenalin and amiodarone. According to the new ACLS guidelines 2015 these are the only drugs remaining in the treatment for shockable rhythms.

​While adrenaline is given for maximum vasoconstriction in order to promote coronary perfusion pressure CPP, amiodarone and sometimes lidocaine are used to promote successful defibrillation of shock-refractory ventricular fibrillation VF or pulseless ventricular tachycardia VT. While the usage of these drugs is undoubtedly very effective in patients with existing circulation the effectiveness during resuscitation remains a matter of debate.

The Effect of Adrenaline

As a matter of fact it has never been proven that adrenalin actually improves long-term outcome. In 2014 Steve Lin and colleagues published a systemativ review on the efficacy of adrenaline in adult out-of-hospital cardiac arrest (OHCA). They were able to show that according to current evidence standard dose adrenaline (1mg) improved rates of survival to hospital admission and return of spontaneous circulation (ROSC) but had no benefit in means of survival to discharge or neurologic outcomes.

What about Amiodarone and Lidocaine?

Kudenchuck et al. now made the effort to look into the efficacy of amiodarone and lidocaine in the setting of OHCA. Used according to the ACLS guidelines 2016 amidarone is given after the third shock applied when treating a shockable rhythm. Two rather small controlled trials have shown so far that using amidarone actually does increase the likelihood of ROSC and the chance to arrive at a hospital alive. It's impact on survival to hospital discharge and neurologic outcome though remains uncertain.

In this randomized, double-blind trial, the investigators compared parenteral amiodarone, lidocaine and saline placebo in adult, non-traumatic, OHCA. They ended up with 3026 patients meeting inclusion criteria and which were randomly assigned to receive amiodarone, lidocaine or saline placebo for treatment. They finally found that neither amiodarone nor lidocaine improved rate of survival to discharge or neurologic outcome significantly. There were also no differences in these outcomes between amiodarone and lidocaine. Across these trial groups also in-hospital care like frequency of coronary catheterisation, therapeutic hypothermia and withdrawal of life-sustaining treatments did not really differ, making a bias due to treatments after admission unlikely.

Take Home

- This study was not able to show any benefit of amiodarone or lidocaine in the the setting of OHCA in terms of survival to hospital discharge and neurologic outcome

- Amiodarone seems to improve the likelihood of ROSC and survival to hospital admission (similar to adrenaline)

- As there are no other options, I believe amiodarone should remain part of the standard treatment for shockable rhythms in OHCA

- Lidocaine can be safely removed from CPR sets as there is no benefit of over amiodarone

As posted on BIJC before, Asad et al. had performed a systematic review on the usage of ketamine as a continuous infusion (>24h) in intensive care patients. The same authors have now published a narrative review providing a more depth discussion about the pharmacological and pharmacokinetic properties of ketamine. Also they present recommendations for dosing and monitoring in an ICU setting.

The Goodies of Ket

Current evidence shows that Ketamine...

- Has no adverse effects on the gastrointestinal tract (bleeding) and does not cause acute kidney injury (compared to nonsteroidal anti-inflammatory drungs, NSAID's)

Take Home

The use of ketamine for analgosedation in the ICU continues to lack high-level evidence.However, it is effectively used around the globe and remains an attractive alternative agent for appropriately selected patients. Taking current knowledge and evidence into account this is especially true for patients with severe pain unresponsive to conventional therapies.

Taking precautions and contraindications into account ketamine is considerably safe and even avoids potentially adverse side effects of other agents used.

The Problem

An endogenous Cushing's syndrome, mostly caused by an adenoma of the pituitary gland, is associated with significant morbidity and mortality when left untreated. The condition is closely associated to life-threatening infections, diabetes mellitus, hypertension and increased risk associated with surgery.

For Cushing's disease the first line therapy is surgical removal of the pituitary tumor. Sometimes though urgent medical therapy is needed first. It has been shown, that surgical risk may be significantly reduced if cortisol concentrations are normalised preoperatively. Conditions requiring urgent cortisol-lowering measures are severe biochemical disturbances (e.g. hypokalaemia), immunosuppression or mental instability.

Medical Treatment Options

​Ketokonazole (yes, the antifungal agent) and metyrapone are used to suppress adrenal steroidogenesis at enzymatic sites. Both agents carry the risk of postential side effects. Mifepristone, a glucocorticoid receptor antagonist, and pasireotide, a new targeted pituitary therapy, are alternative agents. However, they also have their limits and side effects.

Etomidate

​Now that's where etomidate joins the game. Interestingly, etomidate and ketokonazole are chemically closely related... they are both members of the imidazole family. Etomidate is used as an anaesthetic agent since 1972 and became popular for hemodynamic stability and the lack if histamine release. In 1983 a Lancet article noted an increased mortality when etomidate was used in critically unwell patients. In 1984 an article in Anaesthesia first showed a link to low serum cortisol levels caused by etomidate. Until now the discussion continues, whether a single induction dose actually negatively influences patient outcome. A meta-analysis in 2010 was unable confirm this apprehension and the debate continues.

Fact is

Etomidate suppresses the production of cortisol by inhibiting the mitochondrial cytochrome p450-dependent adrenal enzyme 11-beta-hydroxylase and therefore lower serum cortisol levels within 12 hours. In higher doses it also blocks side chain cleavage enzymes and also aldosterone synthase. It might even have anti-proliferative effects on adrenal cortical cells.​On this basis the idea arose, that etomidate might be a useful therapy for severe hypercortisolaemia.

Continuous Etomidate - What's the Evidence

A review article by Preda et al. in 2012 identified 18 publications about the primary therapeutic usage of etomidate in Cushing's syndrome, most of which were case reports. Review of current literature reveals that etomidate indeed suppresses hypercortisolaemia safely and efficiently in patients requiring parenteral therapy. Moreover, etomidate shows a dose-dependent suppression and allows adjustment of the medication to target cortisol levels. At recommended dosages etomidate is considered safe with almost no serious side effects.

The authors conclude, that etomidate is a useful therapeutic option in a hospital setting when oral therapy is not tolerated or inappropriate.​

Take home

- The application of continuous etomidate in Cushing's disease is safe and efficient

- After termination of infusion adrenocortical suppression persists for about 3 hours​- The suspicion, that a single dose of etomidate for rapid sequence inductions might negatively influence patient outcome in the critically ill remains a matter of debate

The discussion on the so called lactic acidosis and its causes has become increasingly interesting over the last couple of years as several biochemical explanations have been challenged. A big confusion persists on the various relationships between lactate, lactic acid and metabolic acidosis.

Most clinicians continue to refer to the classical understanding of impaired tissue oxygenation causing increased lactate production, impaired lactate clearance and therefore resultant metabolic acidosis. Just recently we had a discussion on our ward round on this topic when I was presented the most recent article of UpToDate online on the causes of lactic acidosis. The authors state that 'Lactic acidosis is the most common cause of metabolic acidosis in hospitalised patients' and that 'Lactic acidosis occurs when lactate production exceeds lactate clearance. The increase in lactate production is usually caused by impaired tissue oxygenation...'... finally suggesting that lactate is no good!

These statements support the classical understanding that:- Hyperlactatemia is caused by tissue hypoxemia, and- This in turn then leads to a metabolic acidosis called lactic acidosis

This biochemical understanding has persisted for decades but there are some good reasons to strongly challenge this classical aspect on the 'bad' lactate. Lactate turns out to be by far more complex in its characteristics and functions, so I decided to try and make a short but comprehensive overview on this molecule.

What is lactate?

Lactate is a small organic molecule with the chemical formula CH3CH(OH)CO2H and structurally looks like on the image to the left. It is produced in the cytoplasm of human cells largely by anaerobicglycolysis by the conversion of pyruvate to lactate by LDH. This chemical reaction normally results in a blood lactate to pyruvate ratio of about 10:1. And while lactate is produced, NAD+ also is incurred and this actually can accept protons itself, so does not result in acidosis itself.

Lactate arises from the production of energy by consuming glycogen and glucose.

​Where does it come from?

Typically most people think of muscles first as an origin of lactate. As a matter of fact lactate originates from many other organs, including our red blood cells. Red blood cells always produce lactate as they lack the mitochondria required to regenerate NAD+ needed for glycolysis. In general you can say that tissues with lots of LDH are the main producers of lactate. Around 20mmol/kg/day of lactate are produced under normal circumstances.

Lactate is not only produced in skeletal muscle.

Muscle: 25%Skin: 25%Brain: 20%RBC: 20%Intestine: 10%

What happens with it?

Lactate is not just for nothing. After its production by anaerobic glycolysis lactate is reutilised, for instance in the liver and the cortex of the kidneys. As an example: under the influence of cortisol it is used for gluconeogenesis in hepatocytes and restores glucose and glycogen. Also it is a part of oxidative phosphorylation in the liver, kidney, muscles, the heart and the brain. Like this lactate helps conserve glucose levels in our blood.​​Lactate actually serves as a fuel for oxidation and glucose regeneration and therefore is a source for energy itself.

From The Lancet Endocrinology 2013

​​How does hyperlactatemia develop?

In general you can assume that there is a balance between lactate production and its consumption or usage. The classical understanding that tissue hypoxia leeds to overproduction and underutilisation by impaired mitochondrial oxidation is basically correct.

The key point though is that lactate is also produced via aerobic glycolysis as a response to stress. This happens in septic patients, asthmatic exacerbations, trauma and other critical conditions. In these situations the trigger for lactate production is adrenergic stimulation and NOT tissue hypoxia. There are also several other reasons for hyperlactatemia other than tissue hypoxia:

Also, there is good evidence showing that organs like the lungs are an important producer of lactate during stress. And of course in all these conditions hypoxic and non-hypoxic hyperlactatemia might also co-exist.

In critically ill patients often other reasons than tissue hypoxia are responsible for hyperlactatemia (e.g. adrenergic drive).​

Is lactate harmful?

In contrast to the classical understanding of lactate and lactic acidosis more and more evidence comes up indicating that lactate during stress actually serves as a fuel for energy production. Various tissues, e.g. the myocardium increase their lactate uptake during stress significantly. Also our brain consumes more lactate during stress which is used for oxidation. Research has shown that lactate infusions improve cardiac output in pigs and even in patients with heart failure.

Experimental work on isolated muscles suggests that circulating catecholamines and development of acidic conditions during exhaustive exercise may improve muscles' tolerance to elevated K+ levels. This implies that during high-intensity activity with high extracellular K+ and adrenaline, lactate actually serves as a performance-enhancing chemical, rather than being the cause of muscle fatigue.

Lactate is not harmful for our organism. On the contrary, recent compelling evidence actually suggests that lactate might actually be beneficial, rather than detrimental, during high-intensity activity and to force development in working heart and skeletal muscle.​

Why do critically ill patients with hyperlactatemia die more often then?

In critical care hyperlactatemia indeed is a marker of illness severity and a strong indicator of mortality. This is especially true for patients with sepsis. However, as described above, hyperlactatemia often doesn't indicate hypoperfusion or tissue hypoxia. Hyperlactatemia rather reflects the severity of illness by representing the degree of our body's activation to stress. A fall in lactate concentration following treatment of critically ill patients is due to an attenuation of the stress response rather than to correction of oxygen debt.

​Hyperlactatemia reflects severe disease and the patients response to stress. Patients die due to their illness, not because of a high lactate.​

What about Ringer's lactate?

Ringer's lactate (RL) is not harmful in patients with hyperlactatemia.

As a matter of fact RL turns out to be superior compared to normal saline in hyperlactatemia, acidotic patients and patients with hyperkalemia.​

The bottom line

- Lactate is an indicator of stress, a marker of illness severity and a strong predictor of mortality, but not harmful as a molecule itself.

- Lactate is helpful as an important source of energy and an important fuel for oxidation and glucose generation.

- During conditions like septic shock there is no proof that lactate is produced only due to tissue hypoxia. In fact well ventilated lungs produce a large amount of lactate during sepsis. Lactate in sepsis and other critical conditions is mostly not due to hypoxemia or hypoperfusion.

Dexmedetomidine has shaken up the usual sedatives in ICU but remains a matter of debate among intensivists. One question is whether the higher costs compared to midazolam are justified by clinical advantages. There is research available suggesting that dexmedetomidine might be an attractive alternative to standard sedatives especially in regards of time to extubation and costs (Turinen et al., Jacob et al.). This seems to hold true for moderate to light sedation of intubated patients.

I've stepped over this prospective, double-blind, randomised trial by Riker et al. in which 68 centres in 5 countries recruited intubated 366 patients to received moderate to light sedation with either dexmedetomidine or midazolam. All patients received daily arousal assessment.

Their primary end point was the percentage of time within the target sedation range (RASS score −2 to +1) and this did not differ between the two groups.

Looking at the secondary endpoints though make things a lot more interesting. Just before the beginning of the sedation period both groups had a similar prevalence of delirium. During study drug administration though, the effect of dexmedetomidine treatment on delirium was significant. A reduction of 24.9% with dexmedetomidine is rather impressive (see figure below). This effect was even greater in patients who were CAM-ICU-positive at baseline.

Finally patients on dexmedetomidine had shorter time to extubation (1.9 days in average) while their length of stay on ICU did not differ.

From a safety point of view the most common adverse effect of dexmedetomidine was bradycardia. It's noteworthy that patients on midazolam had more episodes of hypotension and tachycardia.

THE BOTTOM LINE

- This is another study indicating that dexmedetomidine seems to be beneficial in regards of delirium in mechanically ventilated patients and might speed up time to extubation

- Dexmedetomidine is safe in patients where moderate to light sedation is the aim

A good question, but do you actually know. Most ICU's have their standard modes of ventilation and we are busy enough concentrating on the wright PEEP, the perfect tidal volume or prone positioning the patient. But does the mode of ventilation actually have an impact on the outcome? Chacko et al. had a look at exactly this question and performed a systematic review on this topic:

- Early mortality: There is only some moderate-quality evidence suggesting that pressure controlled ventilation might be of benefit, although this was not observed in the long term follow-up!